The goal of this Project is to use functional magnet resonance imaging (fMRI) to evaluate the relationship between age-associated changes in medial temporal lobe (MTL) function (or the function of other brain regions), and age-associated changes in working memory and declarative or explicit memory. MTL neuropathology is closely related to severe declarative memory failure in Alzheimer's disease (AD), but there is growing evidence that milder memory impairment in older individuals is also associated with MTL dysfunction, and that this impairment may signal a preclinical stage of AD, in at least some of these individuals. The primary emphasis will be neural activation that occurs during working memory performance and encoding and retrieval in structures, such as the frontal lobes, and the hippocampal formation as well as parts of the parahippocampal gyrus that comprise the MTL. MTL activation in these areas will be examined for encoding, retrieval (with an emphasis on encoding of successfully and unsuccessfully retrieved items), and compared across groups comprising young and elderly controls, patients with mild cognitive impairment of memory (MCl-memory), and those with mild AD. Secondary emphasis will be neural activation that occurs during encoding and retrieval in other neocortical areas (particular frontal regions). Additional data will include high-resolution structural MRI and high resolution diffusion tensor imaging (DTI) to quantify macro and microstructural volume and integrity of the brain. Part of the latter Project will be carried out in collaboration with Project 1. In collaborative work, the two in vivo projects have demonstrated significant changes in macro- and microstructural white matter integrity in healthy and pathological aging. In this application, Dr. Gabrieli and his collaborators will be able to investigate not only differences in these measures between the four groups, but also the relationship between cognitive performance and regional white matter integrity. In addition, these data will provide important information on the interaction of fMRI signal and changes in global and regional volume and integrity in healthy and pathological aging.